The discovery in the late 1990s of the partnership between the RET receptor tyrosine kinase and the GFRα family of GPI-anchored co-receptors as mediators of the effects of GDNF family ligands galvanized the field of neurotrophic factors, firmly establishing a new molecular framework besides the ubiquitous neurotrophins. Soon after, however, it was realized that many neurons and brain areas expressed GFRα receptors without expressing RET. These observations led to the formulation of two new concepts in GDNF family signaling, namely, the non-cell-autonomous functions of GFRα molecules, so-called trans signaling, as well as cell-autonomous functions mediated by signaling receptors distinct from RET, which became known as RET-independent signaling. To date, the best studied RET-independent signaling pathway for GDNF family ligands involves the neural cell adhesion molecule NCAM and its association with GFRα co-receptors. Among the many functions attributed to this signaling system are neuronal migration, neurite outgrowth, dendrite branching, spine formation, and synaptogenesis. This review summarizes our current understanding of this and other mechanisms of RET-independent signaling by GDNF family ligands and GFRα receptors, as well as their physiological importance.

中文翻译：

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GDNF 配体和 GFRα 受体的 RET 非依赖性信号传导

1990 年代后期，RET 受体酪氨酸激酶与 GPI 锚定共同受体的 GFRα 家族作为 GDNF 家族配体作用介质的伙伴关系的发现激发了神经营养因子领域的发展，牢固地建立了一个新的分子框架，除了无处不在的神经营养因子。然而不久之后，人们意识到许多神经元和大脑区域表达 GFRα 受体而不表达 RET。这些观察结果导致了 GDNF 家族信号传导中两个新概念的形成，即 GFRα 分子的非细胞自主功能，即所谓的反式信号传导，以及由不同于 RET 的信号受体介导的细胞自主功能。被称为 RET 独立信号。迄今为止，GDNF 家族配体的 RET 非依赖性信号通路研究得最好，涉及神经细胞粘附分子 NCAM 及其与 GFRα 共受体的关联。归因于该信号系统的许多功能包括神经元迁移、轴突生长、树突分支、脊柱形成和突触发生。本综述总结了我们目前对 GDNF 家族配体和 GFRα 受体的 RET 独立信号传导机制和其他机制的理解，以及它们的生理重要性。